PTH has multiple, powerful effects on bone but its anabolic actions are poorly understood. In animals, intermittent PTH administration increases both cortical and trabecular bone mass and can prevent, or even reverse, bone loss. The anabolic effects of PTH on bone in humans have been less well studied. In particular the effects of intermittent PTH on cortical bone in humans are unclear and no studies have examined the roles that aging and/or prior bone loss play in the response to intermittent PTH. The former issue is important because cortical bone may be an independent determinant of fracture risk. The latter issue is important because the anabolic effect on trabecular bone in elderly osteoporotic people appears to plateau after about 1 year. We have previously demonstrated that intermittent PTH prevents spinal bone loss in young women rendered acutely estrogen-deficient with GnRH analog therapy. However, because GnRH analog therapy could only be continued for l year, we could not determine the effect of PTH on cortical bone in these women. This proposal will examine the effects of intermittent hPTH-( 1- 34) on bone mass and bone turnover in early menopausal women with normal bone density (BMD). The major aims of this proposal are 1) to determine whether intermittent PTH prevents both cortical and trabecular bone loss in early menopausal women. 2) to assess whether aging and/or prior bone loss is an important determinant of the response to intermittent PTH. and 3) to identify factors that predict the skeletal response to long- term intermittent PTH. 75 early menopausal women with normal BMD will be randomly assigned to treatment with hPTH-( 1-34) 40 ug/day: hPTH-( 1-34) 20 ug/day: or placebo. BMD at sites reflecting cortical and trabecular bone, biochemical markers of bone formation osteocalcin and PICP) and resorption (urinary NTx and DPD) blood cytokines (IL-6, IL-1beta, and TNFalpha), and IGF-I will be monitored at regular intervals for 3 years. The model of early menopausal women with normal BMD is more homogeneous than populations of elderly women with osteoporosis so that studies of PTH in this group are more likely to have interpretable results. Two doses of PTH will be used to determine whether a lower dose can selectively increase bone formation compared to a higher dose which is known to increase bone formation and resorption. By comparing responses in these women with those of elderly osteoporotic women from Dr. Neer's protocol (who receive an identical dose of PTH) we will be able to assess the impact of aging and/or prior bone loss on the skeletal response to PTH. The ability to integrate these proposals in a major advantage of the SCOR structure.